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Dr. Pandji Moeljono, Sp.PD-KEMD Spesialis Penyakit Dalam Konsultan Endokrinologi Metabolik dan Diabet RSAL Dr. Ramelan FK. Universitas Hang Tuah Surabaya
Metabolic syndrome Insulin resistance syndrome Dysmetabolic syndrome Cardiometabolic syndrome Dyslipidemic hypertension Hypertriglycerdemic waist The deadly quartet.
Krans HM., Insulin Resistence and The Metabolic Syndrome, SUMETSU 3, Surabaya, Februari 2007
Waist circumference Waist to hip ratio Reduced HDL cholesterol Elevated Triglycerides Elevated Blood Pressure Urinary Albumin Excretion
In men < 102 cm In women < 88 cm < 0,90 in men < 0,85 in womwn < 1.00 mmol/l in men < 1.30 mmol/l in women > 1.70 mmol/l > 130 / >85 < 0.90 mmol/l in men < 1.00 mmol/l in women > 1.70 mmol/l 140 / 90 > 20 mg/min
In men 94 cm In womwn 80 cm
< 1.03 mmol/l (40 mg/dl) in men < 1.29 mmol/l (50 mg/dl) in women 1.70 mmol/l (150 mg/dl) 130 / 85
Serum glucose
ATP III (Expert panel etc, 2001) American Heart Association (Grundy et al, 2005) World Health Organisation (World Health Organisation, 1999) International Diabetes Federation (Alberti et al, 2005)
1. Lingkar perut
wanita pria 80 cm 90 cm
2. Trigliserida 3. HDLkolesterol
wanita pria
150mg/dL
< 50mg/dL
< 40mg/dL
130/85mmHg 110mg/dL. (sekarang > 100)
Indonesia Clinical setting 2003, of 669 subjects, > 20 years, 35.6% (Adam, Sambo 2003)
Dari 752 DM 58,64% MetS Pria > Wanita = 59% vs 41% (Penelitian di RSAL Dr. Ramelan) (Mulyono P, Perkeni-Makasar, 2005) Penelitian di RSU Dr. Soetomo 60 DM 81,67% Mets (Adi S, Perkeni, 2005
Rural area 2004, of 500 subjects, > 19 years,19.2% (Suastika, 2004) Pre Diabetes 9% and Diabetes 5,2% (n = 5873) (Manaf A, SUMETSU 3, 2007) at Padang Sumatera Barat.
The operational of OBESITY and OVERWEIGHT are based on BMI which is correlated closely with body fatness
Fat distribution in men tend to accumulate in the upper part of the body or in the abdominal region (android obesity), while in women it tends to accumulate in the peripheral part of the body or gluteofemoral region (gynoid obesity)
It is a fact that abdominal fat is more insulin resistance than fat from the other parts
Android Obesity
Gynoid Obesity
1 10
Hyperuricemia 9
Inflammatory Markers 8 (CRP, TNF, IL - 1, IL - 6) Vascular Abnormalities 7 - Urinary Albumin Excretion - Endothelial Dysfunction
IFG IGT
DM
4 Atherogenic Dyslipidemia
Triglycerides HDL-Cholesterol Apolipoprotein-B Small Dense LDL
6 Prothrombotic State
PAI-1 (Esp. Omental Fat) Factor VII Fibrinogen vWF Adhesion Molecules
DIABETES vs PRE-DIABETES
Fasting Blood Glucose Normal < 100 * Pre-Diabetes 100 * 125 Diabetes 126 2 hours post prandial (mg/dl) < 140 140 199 200
Insulin Resistance
Hyperlipidemia
Diabetes
Hypertension
Atherosclerosis
SUMETSU 2007
YAMATO INSTITUTE OF LIFESTYLE-RELATED DISEASES 070217
UKPDS :
100
75
Postprandial Hyperglycemia
Th/Expectation
50
IFG IGT
Facts
T2 DM phase I
25
T2DM phase II
10
14
Dual Defect of T2DM (IR and Impaired AIR) : Treating a Moving Target
Insulin Resistance
T2DM
-cell Dysfunction
-Cell Failure Insulin Concentration Insulin Action Euglycaemia Normal IGT+Obesity or IFG Dx T2DM
Progression to T2DM
Sensitivitas Insulin
30% 50% 70% 100%
Insulin resistance
Glucose intolerance
Increased triglyceride
Increased PAI - 1
PRODUKSI GLUKOSA
Meglitinides ; Repaglinide
Insulin
Thiazolidinediones
Biguanides (Metformin)
SAL. CERNA
alpha-glucosidase inhibitors
ABSORBSI GLUKOSA
Genetic disposition
Prediabetes
Increased insulin resistance and decreased insulin secretion Chronic Hyperlgycemia and hyperinsulinemia Further increase in insulin resistance Gradual decrease in insulin secretion
Manifest diabetes
Advanced diabetes
58
58 31 25
TRIPOD
DREAM
Triglitazone
Rosiglitazone
55
62
Background Metabolic Syndrome (MS) is associated with impaired endothelial function and increased cardiovascular risk. Insulin resistance is a key feature of MS and plays an important role in the pathogenesis of endothelial dysfunction. Aim of the present study was to evaluate the effect of metformin on endothelial function and insulin resistance, assessed by the homeostasis model (HOMA-IR, homeostasis model assessment-insulin resistance),in patients with MS.
Methods.
Sixty-five subjects (37 men and 28 women, mean age 54 6 years) with MS were allocated to receive metformin 500 mg twice daily (n 32) or placebo (n 33) for 3 months. Before and after treatment we assessed endothelial function, using flow-mediated dilatation of the brachial artery, and HOMA-IR.
Results.
Patients who received metformin demonstrated statistically significant improvement in endothelium-dependent vasodilation compared with those treated with placebo (from 7.4 2.1% to 12.4 1.9% vs. 7.3 2.5% to 6.9 2.7%, P 0.0016, metformin vs. placebo respectively), without significant effect on endothelium-independent response to sublingual glyceryl trinitrate (P 0.32).
Metformin improved insulin resistance compared with placebo group (HOMA-IR from 3.39 to 2.5 vs. 3.42 to 3.37; 26% reduction in HOMA-IR, P 0.01). An association between the improvement in insulin resistance and the improvement in endothelial function (r )0.58, P 0.0016) was found.
Conclusion
Metformin improves both endothelial function and insulin resistance in patients with MS. These findings support the central role of insulin resistance in the development of endothelial dysfunction and the role of metformin for the treatment of patients with MS.
7
6 0 15 Conventional 0 3 6 9 Years from randomization Glibenclamide 12 Insulin Metformin
Chlorpropamide
160
140
120
0 0 15 3 6 9 Years from randomization Glibenclamide 12 Insulin Metformin
Conventional
Chlorpropamide
2.5 Conventional
Chlorpropamide
Glibenclamide
Insulin
Metformin
Conventional
Chlorpropamide
Any episode
Major episodes
20
10 0 0 2 4 6 8 10 2
0 0 2 4 6 8 10
0%
Only 31% of individuals achieved good glycemic control (HbA1c 6.5%)1 Only 64% tested for HbA1c within 6 months1 < 50% reached systolic and diastolic blood pressure targets1 Majority had borderline total cholesterol levels (mean = 5.7 mmol/l [220 mg/dl])1 Reduced quality of life associated with:2 insulin use complications
1Liebl
0.2%
CABG
Chen Xingbao, Chinese Health Economics 2003. Tang Ling, China Diabetic Journal 2003.
7.0% 1.5%
Photocoagulation Renal failure
0.4%
Dialysis Peripheral neuropathy
0
Foot ulcer Amputation Blindness
Chen Xingbao, Chinese Health Economics 2003. Tang Ling, China Diabetic Journal 2003.
Proportion (%)
935%*
50 45 40 35 30 25 20 15 10
Proportion of patients (%)
38,580
22.3
313%* 17.7
218%*
11,842 3,726
13.3
5,000
0
5
0
Macrovascular Both micro- and macrovascular
No complications Microvascular
Chen Xingbao, Chinese Health Economics 2003. Tang Ling, China Diabetic Journal 2003.
Too few patients achieved target HbA1c levels, and progression to combination therapy was almost inevitable1
After 3 years of monotherapy, 50% of patients required combination therapy1 Progression of type 2 diabetes was associated with deterioration of glycemic control2
RC, et al. JAMA 1999; 281:20052012. 2UK Prospective Diabetes Study. Lancet 1998; 352:837853.
Sulphonylureas Glibenclamide
TZDs
Metformin
-Glucosidase Inhibitors
Rosiglitazone Pioglitazone
Meglitinides
Repaglinide Nateglinide
Cardiovascular Effects
Vasoprotective : 9
1 2 3 4 5 6 7 8 9 Hyperinsulinemia Platelet Aggregation Erythrocyte Deformability Fibrinolysis (Fibr.; PAI-1; FVII;FXIIIa) Peripheral A Blood Flow Capillary Permeability Carbonyl Stress SMC-Fibroblast Retinal Neovascular
METFORMIN
Lipid : 3
1 Tot-Chol LDL-Chol 2 TG 3 HDL-Chol
*) GLP-1 Degradation (Mannuci et al 2000) Insulin Secretion **) Prevents B-Cells from Gluco- and Lipo-toxicity (Patane et al 2000)
REDUCED
Hypertriglyceridemia AGE-formation Cross-linked Fibrin Neovascularization Oxidative Stress
LIVER
Decreases Hepatic Glucose Production
MUSCLE INTESTINE
Improves Insulin Sensitivity by Increasing Peripheral Glucose Uptake